Effective treatments for motor neuron diseases, such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Kennedy's Disease and Hereditary Spastic Paraplegias (HSP), have yet to be developed. Currently the only FDA-approved drug for treating motor neuron diseases is riluzole. However, riluzole has only moderate success in prolonging patient survival. One possible reason for the lack of effective treatments for motor neuron diseases is that drugs for such diseases were previously developed for humans based on animal models which may not accurately reflect motor neuron diseases in humans. Therefore, establishing a human system to study motor neuron diseases is a crucial step in developing successful therapeutic treatments.
Human Embryonic Stem (hES) cells constantly self-renew and have the potential to grow into any type of cell in the human body. Since little hES research has been conducted, it is not clear whether these cells can be used in scientific models to understand cell death in motor neuron diseases. Therefore, in this study we propose to steer hES cells into becoming motor neurons so that we may gain a better understanding of the aforementioned motor neuron diseases. Because of their self-renewing properties and their ability to be fostered in a scientific environment, our studies of hES cells could provide a useful source of knowledge to develop therapies for patients with motor neuron diseases or spinal cord injuries.
Aim 1: We will take motor neurons from hES cell lines and study their molecular and cellular properties. These studies will allow us to identify how motor neurons express specific genes and proteins. In addition, we will be able to evaulate how effective hES cell-derived motor neurons are in developing treatments for motor neuron diseases. We will also improve the mothod used by the scientific community to induce motor neurons from hES cells. The goal is to develop a reliable method to use hES cells for deriving motor neurons useful for basic research and clinical applications.
Aim 2: We will evaluate toxicity in hES cell-derived motor neurons to test whether human cell cultures can be used as experimental models to investigate motor neuron diseases. We will first analyze how well functional ionotropic glutamate receptors (the basic building blocks of motor neurons in the brain) in these hES-derived motor neurons are expressed using both a pharmacological approach and by recording the electrical activities of motor neurons (electrophysiology). We will then investigate cell death in motor neurons using specific toxins that will target glutamate receptors and transporters. We will also determine the effect of drugs in protecting these cells from toxin-induced death.
Statement of Benefit to California:
The goal of our proposed research is to use hES cells to develop a reliable method for deriving motor neurons. Since hES cells can self-renew and be maintained in vitro the motor neurons derived from hES cells could provide useful knowledge that could be applied to treatments for patients with motor neuron diseases or spinal cord injuries. This proposed research will benefit the State of California and its citizens in several ways. The most obvious way in which this research will benefit Californians is through the reduction of pain and suffering undergone by Californian patients suffering from motor neuron diseases or spinal cord injuries. Caretakers and relatives of those with motor neuron-related medical problems will also experience the benefits. As the state with the largest population in the nation, California spends a enormous amount of money on healthcare for its residents. In the future, finding a cure for neurodegenerative diseases like ALS will significantly reduce state healthcare costs by lessoning the amount of time patients are treated for such diseases. In addition, conducting research in the stem cell field will create job opportunities and attract highly skilled personnel to California. Other states will not be able to attract these workers because of federal restrictions on stem cell research funding. The technologies, drugs, and patents which will result from our studies will allow Californians to be the first people in the country to benefit from stem cell research with respect to its ability to positively affect healthcare, the economy and technological advances.